Methods and compositions comprising desmopressin in combination with an alpha-adrenergic receptor antagonist

ABSTRACT

The invention provides methods and compositions for use of desmopressin in combination with an alpha-adrenergic receptor antagonist. The methods and compositions are useful in the treatment of nocturia and other urinary frequency disorders.

FIELD OF THE INVENTION

The invention provides methods and compositions for use of desmopressinin combination with an alpha-adrenergic receptor antagonist. The methodsand compositions are useful in the treatment of nocturia and otherurinary frequency disorders.

BACKGROUND

Nocturia and other urinary frequency disorders affect a significantportion of the human population. Patients with nocturia experienceinterruption in sleep due to the need to get up during the night tourinate. Patients suffering from overactive bladder often experienceurge incontinence, urgency of urination, and higher urinary frequency.Overactive bladder can be caused by uncontrolled contractions of thebundles of smooth muscle fibers forming the muscular coat of the urinarybladder (the detrusor muscle) during the filling phase of the bladderand is more prevalent in elderly adults.

Compositions and methods for treating nocturia and other urinaryfrequency disorders have been described. For example, U.S. Pat. Nos.7,579,321; 7,799,761; and 8,143,225 describe pharmaceutical compositionsand methods using a low dosage of desmopressin. U.S. patent applicationpublication US 2009/0042970 describes treating nocturia and otherurinary frequency disorders using, for example, transdermaladministration of desmopressin. Also, U.S. patent applicationpublication US 2012/0015880 describes treating nocturia and otherurinary frequency disorders using, for example, intranasaladministration of desmopressin.

One of the challenges in treating nocturia and other urinary frequencydisorders using desmopressin is achieving a therapeutic, but non-toxic,blood plasma concentration of desmopressin. Administering a dose ofdesmopressin that is too large can have severe side effects, such ashyponatremia potentially resulting in seizures or death of the patient.As such, the need exists for compositions and methods which haveimproved safety profiles and/or improved efficacy using a lower dosageof desmopressin. The present invention addresses this need and providesother related advantages.

SUMMARY

The invention provides methods and compositions for use of desmopressinin combination with an antagonist of the alpha-adrenergic receptor. Thiscombination therapy provides benefits to human subjects suffering fromdisorders associated with or featuring undesirable voiding of thesubjects' bladder or frequent urge to void. Such persons may suffer fromoverproduction of urine, inadequate urine concentration, low urineosmolality, excessive frequency of urination (e.g., excessive frequencyof urination associated with central diabetes insipidus), adult primarynocturnal enuresis, nocturia, over-active bladder syndrome (OAB),urinary urgency and frequency during waking hours, incontinence, orunwanted production of urine resulting in urine leakage at rest or byexertion or stress. The desmopressin and alpha-adrenergic receptorantagonist are administered to the subject such that both exertphysiological activity during an overlapping time period. Exemplaryalpha-adrenergic receptor antagonists include, for example, alfuzosin,amosulalol, arotinolol, dapiprazole, doxazosin, ergoloid mesylates,fenspiride, idazoxan, indoramin, labetalol, naftopidil, nicergoline,prazosin, silodosin, tamsulosin, terazosin, tolazoline, yohimbine,phenoxybenzamine, phentolamine, typical and atypical antipsychotics,atipamezole, and pharmaceutically acceptable salts thereof. In certainembodiments, the method optionally further comprises administering a5-alpha reductase inhibitor.

Accordingly, one aspect of the invention provides a method of inhibitingthe urge to urinate in a human subject over an interval of about twohours to no more than about eight hours. The method comprisesadministering to a human subject in need thereof an effective amount ofdesmopressin and an alpha-adrenergic receptor antagonist so that bothexert physiological activity during an overlapping time period. Thedesmopressin and antagonist components may be administered separately ortogether. Typically, the desmopressin component is taken a short time,e.g., about one half hour, before the period of urination avoidance isto begin. The antagonist component may be taken at the same time, oralternatively at some point well before administration of thedesmopressin. The dosage of desmopressin and/or alpha-adrenergicreceptor antagonist and/or the dosing regimen may be adjusted so thatthe method inhibits the urge to urinate in a human subject over aninterval of about 4 hours to about 7 hours. The desmopressin isadministered at a dosage such that the subject does not experiencehyponatremia, a harmful condition in which the sodium concentration inthe subject's plasma is too low, e.g., below about 135 mmol/L.Hyponatremia is avoided provided the maximum dose of desmopressin in theblood is less than 10 pg/ml, preferably less than 5 pg/ml, and mostpreferably less than 5 pg/ml, e.g., 2 or 3 pg/ml. Severe hyponatremiacan result in electrolyte abnormalities that can cause cardiacarrhythmias, heart attack, seizures, and/or stroke. Preferably, theantagonist is administered at a dosage below that directed on its label(for approved drugs) or recommended in clinical practice to treat OABwhen used alone for that purpose. This tends to reduce side effects ofsuch alpha-adrenergic receptor antagonists. The combination therapy hasbeen shown to effectively treat nocturia reliably and safely. In certainembodiments, the method optionally further comprises administering a5-alpha reductase inhibitor. Another aspect of the invention provides amethod of safely inducing an antidiuretic effect over a short intervalin a human subject. The method comprises administering to a humansubject in need thereof an effective amount of desmopressin and analpha-adrenergic receptor antagonist so that both exert physiologicalactivity during an overlapping time period. In certain embodiments, themethod optionally further comprises administering a 5-alpha reductaseinhibitor, such that, for example, each of desmopressin, thealpha-adrenergic receptor, and 5-alpha reductase inhibitor exertphysiological activity during an overlapping time period.

Another aspect of the invention provides a pharmaceutical compositioncomprising desmopressin, an alpha-adrenergic receptor antagonist, and apharmaceutically acceptable carrier. In certain embodiments, thepharmaceutical composition is formulated for transmucosaladministration, e.g., buccal or nasal administration to a human subject.In other embodiments the composition is formulated as a transdermal orintradermal patch. In other embodiments the alpha-adrenergic receptorantagonist is taken orally while the desmopressin is takentransmucosally, e.g., sublingually or intranasally.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a graph of desmopressin blood concentration and variable fluxrate versus time illustrating a 7-hour operation of a device and method.

FIG. 2 is a graph of desmopressin blood concentration and constant fluxrate versus time illustrating a 7-hour operation of a device and methodaccording to an alternative embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods and compositions for use of desmopressinin combination with an alpha-adrenergic receptor antagonist. Thiscombination therapy provides benefits to subjects suffering fromdisorders associated with or featuring undesirable voiding of asubject's bladder of frequent urge to void. Such subjects may sufferfrom overproduction of urine, inadequate urine concentration, low urineosmolality, excessive frequency of urination (e.g., excessive frequencyof urination associated with central diabetes insipidus), adult primarynocturnal enuresis, nocturia, urinary urgency and frequency duringwaking hours, over-active bladder syndromes (OAB), incontinence, orunwanted production of urine resulting in urine leakage at rest or byexertion or stress. The desmopressin and alpha-adrenergic receptorantagonist are administered to the subject such that both exertphysiological activity during an overlapping time period. The antagonistmay be administered at doses below those used in current clinicalpractice, for the treatment of BPH.

Various aspects of the invention are set forth below in sections;however, aspects of the invention described in one particular sectionare not to be limited to any particular section.

Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a,” “an” and “the” as used herein mean “one or more” andinclude the plural unless the context is inappropriate

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for therapeutic use in vivo or exvivo.

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

The terms “subject” and “patient” are used interchangeably and refer tohumans, especially adult male humans.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

I. Therapeutic Methods

The invention provides therapeutic methods using desmopressin incombination with an alpha-adrenergic receptor antagonist. Thiscombination therapy provides benefits to subjects suffering fromdisorders associated with or featuring undesirable frequent urges tovoid a subject's bladder. As described above, such subjects may sufferfrom overproduction of urine, inadequate urine concentration, low urineosmolality, OAB, excessive frequency of urination (e.g., excessivefrequency of urination associated with central diabetes insipidus),adult primary nocturnal enuresis, nocturia, urinary urgency andfrequency during waking hours, incontinence, or unwanted production ofurine resulting in urine leakage at rest or by exertion or stress. Thedesmopressin and alpha-adrenergic receptor antagonist are administeredto the subject such that both exert physiological activity during anoverlapping time period. Desirably, administration of desmopressin andthe alpha-adrenergic receptor antagonist results in a synergisticeffect. Exemplary benefits from such a synergistic effect includeimproved reduction in a subject's urge to urinate and/or a reduction inthe amount of desmopressin and/or antagonist needed to achieve atherapeutic effect. Furthermore, administration of reduced amounts ofthe alpha-adrenergic receptor antagonist relative to the doses usedclinically to treat BPH means that side effects of these drugs arereduced. In certain embodiments, the method optionally further comprisesadministering a 5-alpha reductase inhibitor.

One aspect of the invention provides a method of inhibiting the urge tourinate in a human subject over an interval of about two hours to nomore than about eight hours. The method comprises administering to ahuman subject in need thereof an effective amount of desmopressin and analpha-adrenergic receptor antagonist so that both exert physiologicalactivity during an overlapping time period. The dosage of desmopressinand/or alpha-adrenergic receptor antagonist and/or the dosing regimenmay be adjusted so that the method inhibits the urge to urinate in ahuman subject over certain intervals. For instance, in certainembodiments, the method inhibits the urge to urinate in a human subjectfor an interval of about 4 hours to about 6 or 7 hours. Variousembodiments of the method (e.g., dosage and route of administration ofdesmopressin, the alpha-adrenergic receptor antagonist, the targetpatient population, and exemplary benefits of the combination therapy)are described in the sections below. In certain embodiments, the methodoptionally further comprises administering a 5-alpha reductaseinhibitor, such that, for example, each of desmopressin, thealpha-adrenergic receptor, and 5-alpha reductase inhibitor exertphysiological activity during an overlapping time period.

Another aspect of the invention provides a method of inducing anantidiuretic effect in a human subject. The method comprisesadministering to a human subject, e.g., an adult male or female, in needthereof an effective amount of desmopressin and an alpha-adrenergicreceptor antagonist so that both exert physiological activity during anoverlapping time period. The method can be further characterizedaccording to the interval over which an antidiuretic effect is provided.For instance, in certain embodiments, an antidiuretic effect is achievedover an interval of about two hours to no more than about seven hours(or eight hours). In certain other embodiments, the antidiuretic effectis achieved over an interval of about four hours to about six hours.Various embodiments of the method (e.g., dosage and route ofadministration of desmopressin, dosage and route of administration ofthe alpha-adrenergic receptor antagonist, patient population, andexemplary benefits of the combination therapy) are described in thesections below. In certain embodiments, the method optionally furthercomprises administering a 5-alpha reductase inhibitor, such that, forexample, each of desmopressin, the alpha-adrenergic receptor, and5-alpha reductase inhibitor exert physiological activity during anoverlapping time period.

In certain embodiments, for the avoidance of the urge to urinateovernight, the method comprises administering to the subject analpha-adrenergic receptor antagonist on a daily basis (e.g., for aperiod of at least about a month) and administering desmopressin beforethe subject retires to sleep. In certain other embodiments, the methodcomprises administering to the subject an alpha-adrenergic receptorantagonist at a dose level lower than its smallest drug labelrecommended dose for treatment of BPH and administering desmopressinbefore the subject retires to sleep. In yet other embodiments, themethod comprises administering to the subject as a mixture before thesubject retires to sleep desmopressin and an alpha-adrenergic receptorantagonist at a dose level lower than the smallest drug labelrecommended dose of said antagonist for treatment of BPH.

Desmopressin

The term “desmopressin” refers to 1-desamino-8-D-arginine vasopressinand includes the free base form and pharmaceutically acceptable saltsand hydrates thereof. One exemplary commercially available salt form isan acetate salt. Desmopressin, 1-desamino-8-D-arginine vasopressinmonoacetate, also known as DDAVP, is described in, for example, U.S.Pat. No. 3,497,491, and is commercially available as a prescriptionmedication sold, for example, under the names DesmoMelt, Stimate,Minirin® and DESMOSPRAY®.

Desmopressin as an active pharmaceutical ingredient also is availablecommercially for formulation into new drug dose forms and compositions.The dosage of desmopressin administered to a human subject can beselected based on the weight of the subject and the desired durationover which a therapeutic effect is desired. The dosage can becharacterized according to the blood plasma concentration ofdesmopressin achieved.

Accordingly, therapeutic methods described herein can be characterizedaccording to the blood plasma concentration of desmopressin achieved. Incertain embodiments, the administering achieves in the human subject ablood plasma concentration of desmopressin that does not exceed 15pg/mL. In certain other embodiments, the administering achieves in thehuman subject a blood plasma concentration of desmopressin in the rangeof about 0.2 pg/mL to about 5 pg/mL. In yet other embodiments, theadministering achieves in the human subject a blood plasma concentrationof desmopressin in the range of about 0.5 pg/mL to about 2.5 pg/mL. Inyet other embodiments, the administering achieves in the human subject ablood plasma concentration of desmopressin in the range of about 0.5pg/mL to about 1.5 pg/mL. Generally, the amount of desmopressin thatreaches the bloodstream from administration of a given specific doseform should not exceed 2 ng/kg of body weight, and can be as low as 0.5ng/kg, 1.0 ng/kg, or 1.5 ng/kg.

Desmopressin can be administered using traditional routes ofadministration. For example, in certain embodiments, desmopressin isadministered transdermally, intradermally, transmucosally, or evenpossibly orally, although the variability of the bioavailability of oraldoses is so great that consistent very low blood concentrations are hardor impossible to achieve reproducibly. In certain other embodiments,desmopressin is administered transdermally, intradermally, ortransmucosally. In yet other embodiments, desmopressin is administeredtransdermally. In still other embodiments, desmopressin is administeredintranasally.

When desmopressin is administered transdermally or intradermally, themethod can be characterized according to the rate at which desmopressinis passed through the skin of a human subject. For example, in certainembodiments, desmopressin is administered at a first flux ratesufficient to achieve rapidly a desired blood plasma concentration ofdesmopressin, e.g., less than five, preferably less than 2 pg/ml, andthen at a second, lower flux rate sufficient to maintain the firstattained blood plasma concentration for a desired interval, e.g., sixhours. In certain embodiments, the method is further characterized by aflux range, such as where desmopressin is administered at a flux rateranging from about 5 ng/hour to about 35 ng/hour. In yet otherembodiments, desmopressin is administered at a flux rate ranging fromabout 5 ng/hour to about 35 ng/hour. In still other embodiments,desmopressin is administered at a flux rate ranging from about 5 ng/hourto about 15 ng/hour.

Various devices and methods for administering desmopressin have beendescribed previously and are contemplated for use in the presentinvention. See, for example, U.S. Patent Application Publication Nos. US2009/0042970 and US 2012/0015880, each of which are hereby incorporatedby reference. One device that may be used to administer desmopressin hasa depot containing a solution of desmopressin in a pharmaceuticallyacceptable carrier. An interface member for application to the skin of apatient, such as a permeable pad for attachment to the skin, or one oran array of microneedles, are in fluid communication with the depot. Thedevices comprise various means for delivering the desmopressin solutionfrom the depot to the interface member and downstream intradermally ortransdermally to the blood of a patient. The flux rate of thedesmopressin is controlled by setting the concentration of desmopressinin the depot, in combination with controlling either the rate of flow ofsolution from the depot, the rate of flow of solution to the interfacemember, the rate of flow of solution from the interface member into thebody of the patient, or by exploitation of some combination of thesecontrol points. In any event, the influx rate is controlled to besufficient to establish a desmopressin concentration in the blood of thepatient just above the water channel activation threshold, e.g., withinthe range of 0.1 to about 2.5 pg/ml, advantageously no greater than 1,1.5, 2, or 2.5 pg/ml. The flux rate in any case is insufficient toinduce a desmopressin concentration in the blood of the patient to alevel greater than about 10 pg/ml. The flux rate may be between about 5,10, 15, 20, 25, or 30 to 35 ng/hr (i.e., 5000, 10,000, 15,000, 20,000,25,000, or 30,000 to 35,000 pg/hr), advantageously about 10-20 ng/hr or20-35 ng/hr, more advantageously about 5-15 ng/hr, so as to establishthe desired blood concentration for a reasonable, predetermined timebefore the patient or the device shuts off desmopressin flow.

The dosage of desmopressin and/or duration of a therapeutic blood plasmaconcentration of desmopressin necessary to achieve a therapeutic effectis desirably less when desmopressin is used together with thealpha-adrenergic receptor antagonist than when desmopressin isadministered alone, and the urge to void is reduced as compared to whenthe alpha-adrenergic receptor antagonist is administered alone. Forexample, in certain embodiments, the alpha-adrenergic receptorantagonist may reduce the urge to urinate for a period of time afterwhich the desmopressin blood plasma concentration drops below thethreshold necessary to achieve antidiuresis (activation of waterchannels in the kidney). As another example, the physiological effect ofthe alpha-adrenergic receptor antagonist in combination with less urinefilling the bladder during the interval of induced antidiuresis togetherhave the effect of decreasing the patient's urge to urinate.

With respect to intradermal or transdermal administration, the flux rateof desmopressin preferably is set so that, given the desired bloodconcentration and the known clearance rate of desmopressin (half-life ofabout 1.5 to 2.0 hours), the patient reaches the desired low butsupra-threshold blood concentration in a reasonable time, e.g., lessthan an hour (and generally, the sooner, the better), and is maintainedwithin a low dose range just above the activation threshold(approximately within the range of 0.5 to 1.5 pg/ml) for a desired timeperiod (e.g., two hours for a workout, or 4-6 hours or 5-8 hours fortreatment of nocturia). Termination of the flux by automatic or manuallyactuated mechanisms built into the device, or by removal of the devicefrom contact with the skin, results in normal drug clearance mechanismsof the body of the patient rapidly reducing the low concentration to astill lower concentration, below the activation threshold.

The interface member of the device may comprise a desmopressinsolution-permeable membrane defining a surface for contact with the skinof the patient. The desmopressin solution-permeable surface permitsdelivery of the desmopressin from the depot through or to the skin ofthe patient. For highest bioavailability and precision of delivery,intradermal delivery is preferred. Intradermal delivery permits directdelivery to a vascularized compartment resulting in rapid absorptioninto the systemic circulation and correspondingly rapid on/off effects.While transdermal delivery is contemplated, its use is more subject tovariable bioavailability due to the stratum corneum functioning as aphysical barrier to drug reaching the epidermis, and to the creation ofa depot of drug in the epidermis.

Accordingly, transdermal delivery methods and devices can benefit fromtechniques that reduce the efficacy of the stratum corneum as a barrierto drug entry. The skin can also be “micropunctured” to introduce“micropassages” or “microfissures” across the stratum corneum, toenhance subsequent transdermal delivery, e.g. by one or moremicroneedles as described below.

The permeability of the stratum corneum can also be enhanced through useof a chemical permeability enhancer, such as dimethylsulfoxide,decylmethylsulfoxide, diethylene glycol monomethyl ether,diethyleneglycol monoethyl ether, sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, benzalkonium choride, lecithin (see, forexample, U.S. Pat. No. 4,783,450, which is hereby incorporated byreference), 1-n-dodecylazacycloheptan-2-one (see, for example, U.S. Pat.Nos. 3,989,816; 4,316,893; 4,405,616; and 4,557,934, all of which arehereby incorporated by reference), ethanol, propanol, octanol, benzylalcohol, lauric acid, oleic acid, valeric acid, isopropyl myristate,isopropyl palmitate, methylpropionate, ethyl oleate, propylene glycol,ethylene glycol, glycerol, butanediol, polyethylene glycol, polyethyleneglycol monolaurate, urea, hydroxide (see, for example, U.S. Pat. No.6,558,695, which is hereby incorporated by reference),dimethylacetamide, dimethylformamide, 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, triethanolamine,salicylic acid, citric acid, succinic acid, and permeability enhancingpeptides (see, for example, U.S. Pat. No. 5,534,496, which is herebyincorporated by reference).

An efficient means of desmopressin delivery from the depot to the skinis intradermal administration, via an interface member comprising one ormore microneedles which penetrate the stratum corneum of the patient andenable fluid communication between the depot and the epidermis or directcontact with surfaces or cavities in the microneedles coated with orcontaining desmopressin. The length and size of the microneedles areadequate to penetrate the stratum corneum but small enough to producelittle if any sensation for the patient. For example, suitable lengthsare about 0.3 to 1.5 mm, advantageously between about 0.8 to 1.1 mm. Anexample of a single needle device is provided in U.S. Pat. No.6,939,324, which is herein incorporated by reference.

A plurality of microneedles, e.g., in an array, may be desirable if moresurface area for delivery, or a more flexible patch, is desired. Themicroneedles may each have a channel that transports fluid from thedepot to the needle end, or the microneedles may otherwise allow forfluid delivery from the depot, e.g., with perforated or porous walls.Alternatively, the microneedles may be coated with a desmopressinpreparation or contain a film or matrix of desmopressin in cavities orin the material structure of the microneedle itself, to provide a burstof desmopressin upon application so as to aid rapid achievement of thethreshold activating concentration, optionally with desmopressinsolution passing through the needles to help achieve, or to maintain thedesired concentration.

The use of dissolvable microneedles is also contemplated, as their useavoids, in some cases, pain and/or irritation caused by metal needles orpiercing elements. U.S. Pat. No. 7,182,747, for example, discloses“solid solution perforators” which may be adapted for use in theinventions disclosed herein. In contrast to conventional hollow needletechnologies, these microneedles are made from a solid matrix ofdissolvable or biodegradable material that optionally holds one or moreselected drugs and is formed into one or more perforators.

Another device for delivering desmopressin is a patch that the userapplies before sleep, or before some other interval of activity wherethe patient desires to interrupt urine production. The patch may butneed not necessarily include an active solution flow control mechanism,e.g., with a user-selectable timing function, so the user can choose thelength of time he wishes to have normal urine production suppressed,i.e., in the case of sleep, roughly equivalent to or shorter than thedesired sleep time. The patient removes the patch from its packaging,sets the delivery time if necessary, and applies the patch to an area ofthe skin. Desmopressin delivery at the levels and rates described hereinthen begins, and urine production is suppressed for the desired time.When the flow controller is shut off, the patch is removed, or thedesmopressin depot is exhausted, normal urine production returnsquickly. In a preferred simple version of the device, the amount ofdesmopressin in the depot and its engineered flux rate throughexhaustion of the depot fixes the delivery time, e.g., five to sevenhours, with termination of flux corresponding simply to exhaustion ofthe patch delivery. Thus, the patient can sleep without having to wakeperhaps repeatedly during the sleep hours, or engage in other activitywithout concern about involuntary voiding.

Turning to the drawings, the operation of exemplary devices will bedescribed.

FIG. 1 illustrates operation of an exemplary embodiment of the inventionin treating a patient for whom shutting off urine production is desired,e.g., treating nocturia. A device according to the invention thatdelivers a low dosage/low variable flux of desmopressin to a patient isaffixed to the skin of the patient, the patient urinates, and the deviceis activated at 10:00 P.M. FIG. 1 shows illustrative and exemplary blooddesmopressin concentrations and the flux rates for this patient atvarious times following application or activation of the device. At onehour (11:00 P.M.), the desmopressin flux rate has peaked at about 20ng/hr and has raised the patient's blood desmopressin concentration toover about 1.0 pg/ml, i.e., above the concentration sufficient toactivate kidney water channels and to induce an antidiuretic effect(here illustrated as being at a blood concentration of about 0.8 pg/ml).At 2 hours (midnight), the flux rate is decreasing slightly but is stillin the 20 ng/hr range, and blood desmopressin concentration is elevatedto about 1.5 pg/ml. These values decrease slowly but are relativelyconstant for the next 2.5 to 3 hours. After about 5 hours (3:00 AM), theflux rate has decreased to a level where the activation concentration ofdesmopressin cannot be sustained. As the flux rate continues to drop,the blood desmopressin concentration falls below the water channelactivation level, and urine production commences (here at about 3:45AM). By 5:00 AM blood concentration is below about 0.5 pg/ml and fluxrate has dropped to zero. By 6:00 AM the patient is awake and feels anormal urge to void as urine has been produced for the last hour and ahalf or so of sleep. During the sleep there is a sustained antidiureticinterval, little or no urine production, and no bothersome orsleep-interrupting urge to void. The flux rate of desmopressin and theblood concentration of desmopressin may be more or less depending on thedosage of alpha-adrenergic receptor antagonist administered to thepatient. It is appreciated that the desmopressin and alpha-adrenergicreceptor antagonist may be administered to the patient in separateformulations, or the desmopressin and alpha-adrenergic receptorantagonist may be mixed together to form a single formulation that isadministered to the patient.

FIG. 2 illustrates another exemplary embodiment of the invention fortreating a patient to shut off urine production, e.g., treatingnocturia. A device according to the invention that delivers a low dosageconstant flux of desmopressin is affixed to the skin of the patient. Thedevice is activated (if necessary) and the patient urinates at 10:00 PM.FIG. 2 shows illustrative and exemplary blood desmopressinconcentrations resulting from a flux of about 10 ng/hr over about a fivehour infusion from 10:00 PM to 3:00 AM relative to the threshold bloodconcentration for desmopressin's antidiuretic effect. Within about anhour from flux initiation the blood desmopressin concentration exceedsthe threshold level and begins to exert an antidiuretic effect. Theblood concentration approaches a more or less stable range within abouttwo to three hours (between about 1.0 and 1.5 pg/ml) which is sustainedduring the remainder of the five hour flux until 3:00 AM. At this timethe flux is discontinued (e.g., timed out or exhausted). Now the blooddesmopressin concentration decreases from clearance mechanisms inaccordance with the drug's elimination half-life, falling below thethreshold approximately two hours later (5:00 AM). By 7:00 AM thepatient has produced urine, and wakes to void. The flux rate ofdesmopressin and the blood concentration of desmopressin may be more orless depending on the dosage of alpha-adrenergic receptor antagonistadministered to the patient.

The foregoing examples are for illustrative purposes only. Theactivation concentration will of course vary among individuals, as willblood volume. The important principle in the operation of the device isthat the antidiuretic effect can be controlled safely, as theantidiuretic action is maintained by maintaining a low desmopressinconcentration by a continuous low influx of the drug, and aninterruption of the influx permits the body to rapidly clear the drugand to re-establish normal urine production. This means that the patchdevices enhance safety of desmopressin administration, with little or norisk of development of water intoxication when used as directed.

In accordance with the invention, the alpha-adrenergic receptorantagonist may be present in admixture with the desmopressin in thepatch devices described above, or with the intranasal dose formdisclosed below, but preferably is supplied as a daily oral dose, and isactive and present in the blood plasma during the time the desmopressinis present.

An exemplary device for intranasal administration of desmopressin is asafety dispenser for inducing in members of a target patient populationan antidiuretic effect while reducing the risk that a member of thepopulation may develop hyponatremia. The dispenser comprises a reservoirhaving disposed therein a composition comprising a preparation ofdesmopressin and a nasal membrane permeation enhancer in an amountsufficient to constitute multiple drug doses. The reservoir is incommunication with an outlet and is fitted with a pump, preferably adisposable pump, and preferably one that can be actuated manually, suchas a squeeze bottle actuated dispenser, or a plunger pump fitted onto aglass bottle. The pump enables serially dispensing multiple metereddoses from the reservoir through the outlet in the form of a spray intoa nostril or nostrils of a patient so as to deposit a dose of consistentsize onto an intranasal mucosal or other surface.

Each spray comprises a multiplicity of droplets, preferably with anaverage volume distribution in the range of 20 μm for D10 to about 300μm for D90. This means that about 10% of the droplets are smaller thanabout 20 μm in diameter and 90% are smaller than 300 μm in diameter.Each spray dose is preferably of a weight and desmopressin concentrationsuch that it comprises between 0.5 ng desmopressin per kilogram of thepatient's body weight and 75 ng desmopressin per kilogram of thepatient's body weight. The spray is characterized by a desmopressinbioavailability greater than about 5%, that is, between about 5% and 25%of the active in the composition actually enters the patient'sbloodstream and contributes to the drug effect, and the remainder isdegraded, typically by digestion. Generally, the higher thebioavailability of a spray, the less desmopressin per spray needs to bedelivered into a nasal cavity, and vice versa, the goal being to achievemore consistently a target desmopressin maximum blood concentration(C_(max)) in members of the patient population.

The combination of properties of the spray dispenser and the compositionit contains enables respective doses of spray to be effective torestrict the concentration of desmopressin produced in the bloodstreamof patients, on a per kilogram basis, to a relatively narrow range,thereby to achieve a relatively consistent, time limited duration ofantidiuresis. Stated differently, respective successive spray dosesestablish in a patient by drug transport across intranasal mucosalmembranes a C_(max) of desmopressin which is relatively consistent. Theamount of drug delivered to the bloodstream for repeated doses from thesame dispenser to the same person preferably should differ no more than100%, and preferably less than 50%. The dispenser's coefficient ofvariation is similar to the coefficient of variation of C_(max) producedby serial subcutaneous doses of desmopressin designed to achieve thesame target C_(max). Preferably, respective successive spray doses aresufficient to establish in a patient by intranasal delivery a C_(max) ofdesmopressin having a coefficient of variation within about 50%, morepreferably about 25%, of the coefficient of variation of C_(max)produced by a subcutaneous bolus of desmopressin designed to achieve thesame target C_(max).

The value of the target C_(max) may be varied, depending on the durationof the antidiuretic interval the dispensed composition is designed toinduce and the dosage of alpha-adrenergic receptor antagonist. Forexample, a product designed for a 7-8 hour interval of urine productionsuppression might be designed to deliver a C_(max) of no more than15+/−3 pg/ml. Thus, by way of illustration, a 7 hour product might havea bioavailability of 10% and a desmopressin load per spray of 0.75 μg or750 ng. This would mean that about 75 ng of drug would reach thepatient's bloodstream, and that a 70 kg (˜155 lb.) adult would receive adose in his bloodstream of about 1.0 ng/kg, and achieve a target C_(max)of less than about 5 pg/ml. Another embodiment of the same product mighthave a bioavailability of 8% and a desmopressin load per spray of 2.0 μgor 2000 ng, delivering about 160 ng drug to the patient's bloodstream asan effective dose of 160 ng/75 kg or slightly more than 2 ng/kg, and thetarget C_(max) of less than about 10 pg/ml. Another exemplary productmay be designed for a 3-4 hour urine interruption and might deliver aC_(max) of no more than about 3 pg/ml.

Alternatively, a single dispenser which delivers, e.g., 200 ng or 500 ngper spray, when used in accordance with package insert or physicianinstructions, may serve to achieve, for example, different durations ofantidiuresis in the same person or the same duration of antidiuresis inadults of different weight, simply by varying the number of spraysdelivered per administration event. Typically, about 20 minutes to anhour after administration of the pharmaceutical composition of thepresent invention, the mean urine output per minute in a treatedindividual decreases to less than about 4 ml/minute, preferably lessthan about 1 ml/min, and stays in this low range for a desired timeperiod, such as 180 minutes, 240 minutes, 300 minutes, 360 minutes, or420 minutes. About twenty minutes after administration, the mean urineosmolarity is greater than about 300 mOsmol/kg and remains at highconcentration for a period of time ranging up to 180 minutes, 240minutes, 300 minutes, 360 minutes, or 420 minutes.

One important property of the intranasal administration is that itconsistently deliver per spray a maximum blood concentration within arelatively narrow time and dose range, and therefore avoids or minimizesaccidental delivery of a larger dose resulting in a longer than expectedantidiuretic effect and the possibility of induction of hyponatremia.Consistent delivery, as the phrase is used herein, should be taken tomean repeatable within a range similar to the range observed whenadministering very low doses of desmopressin by subcutaneous injection,or perhaps somewhat greater. Such consistency generally is achieved moreeasily exploiting formulations with higher bioavailability, andaccordingly a bioavailability of at least 5%, preferably at least 10%,more preferably at least 15%, and preferably even higher is preferred.Higher bioavailability is achieved by exploiting formulation technology,especially the use of permeation enhancers, and by chemical engineeringof the spray composition as disclosed herein.

In one embodiment, the dispenser may further comprise means for blockingdispensing of a second desmopressin spray, or series of sprays above acertain dose, e.g., above about a dose sufficient to produce a bloodconcentration above about 10 to 12 pg/ml, for a predetermined timeinterval after dispensing a first dose. This can be achieved passivelyas a consequence of the design of the spray mechanism as disclosed, forexample, in U.S. Pat. No. 7,335,186, the disclosure of which isincorporated herein by reference. Alternatively, an active timer,powered by a battery, mechanical spring, or compressed gas within thedispenser, may be included together with mechanisms known per sedesigned to preclude a second dispensing until passage of apredetermined interval, e.g., 8 hours, or somewhere between 6 to 24hours. Such a mechanism can discourage abuse of the product and furtherminimize the chances that a patient may inadvertently or intentionallyself-induce antidiuresis for too long.

Exemplary permeation enhancers for use in the formulation are “Hsiehenhancers” (see U.S. Pat. No. 5,023,252) available commercially fromCPEX Pharmaceuticals (formerly Bentley) of Exeter, N.H. Preferred withinthe class of Hsieh enhancers useful in the articles of manufacture arethose disclosed in U.S. Pat. No. 7,112,561, and the currently mostpreferred are disclosed in U.S. Pat. No. 7,244,703, such ascyclopentadecanolide, known in the trade as CPE-215. Many otherenhancers may be used.

In some embodiments, the invention provides uses of the safety dispenserto induce an antidiuretic effect. The dispenser and desmopressinformulation may comprise any of the properties described herein. Forexample, in one embodiment, the desmopressin C_(max) is directlyproportional to the amount of nasally administered desmopressin over aC_(max) ranging from about 0.5 pg/ml to about 10.0 pg/ml. The value ofthe target C_(max) may be varied, depending on the duration of theantidiuretic interval the dispensed composition is designed to induceand the dosage of alpha-adrenergic receptor antagonist. For example, useof a safety dispenser described herein may produce antidiuresis for lessthan about 8 hours, less than about 6 hours, for between about 2 and 4hours, or for between about 4 and 7 hours. Another exemplary use of aproduct may be designed to deliver a C_(max) in a patient of no morethan about 15 pg/ml, 10 pg/ml, 7 pg/ml, or 3 pg/ml.

Alpha-Adrenergic Receptor Antagonists

Alpha-adrenergic receptor antagonists are a class of medicinal agentsthat are antagonists of the alpha-adrenergic receptor. Alpha-adrenergicreceptor antagonists are sometimes referred to as alpha-blockers.Exemplary alpha-adrenergic receptor antagonists include alfuzosin,doxazosin, idazoxan, prazosin, silodosin, tamsulosin, terazosin,tolazoline, yohimbine, and pharmaceutically acceptable salts thereof. Abrief description of each of these potentially suitable alpha-adrenergicreceptor antagonists is provided below.

Alfuzosin

Alfuzosin has the chemical nameN-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide.A pharmaceutically acceptable salt of alfuzosin may be used. Forexample, the hydrochloride salt of alfuzosin is commercially availableunder the trademark UROXATRAL® in tablet form. Alfuzosin may beadministered via routes known in the art, such as by oraladministration. The amount of alfuzosin or a pharmaceutically acceptablesalt thereof administered to the patient can be in the range of, forexample, about 1 mg to about 100 mg per day. In certain embodiments,alfuzosin is administered (e.g., orally) at a daily dosage ranging fromabout 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg toabout 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg,about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg toabout 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, orabout 90 mg to about 100 mg. In certain other embodiments, alfuzosin isadministered (e.g., orally) at a daily dosage ranging from about 7.5 mgto about 12.5 mg, about 9 mg to about 11 mg, or about 9.5 mg to about10.5 mg.

Doxazosin

Doxazosin has the chemical name1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]piperazine.A pharmaceutically acceptable salt of doxazosin (e.g., doxazosinhydrochloride or doxazosin mesylate) may be used. For example, themesylate salt of doxazosin is commercially available under the trademarkCARDURA® in tablet form. Doxazosin may be administered via routes knownin the art, such as by oral administration. The amount of doxazosin or apharmaceutically acceptable salt thereof administered to the patient canbe in the range of, for example, about 0.1 mg to about 50 mg per day. Incertain embodiments, doxazosin is administered (e.g., orally) at a dailydosage ranging from about 0.1 mg to about 0.5 mg, about 0.5 mg to about1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about 2.0 mg,about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0 mg, about 3.0 mgto about 3.5 mg, about 3.5 mg to about 4.0 mg, about 4.0 mg to about 4.5mg, about 4.5 mg to about 5.0 mg, about 5.0 mg to about 5.5 mg, about5.5 mg to about 6.0 mg, about 6.0 mg to about 6.5 mg, about 6.5 mg toabout 7.0 mg, about 7.0 mg to about 7.5 mg, about 7.5 mg to about 8.0mg, about 8.0 mg to about 9.0 mg, about 9.0 mg to about 10 mg, about 10mg to about 12 mg, about 12 mg to about 14 mg, about 14 mg to about 16mg, about 16 mg to about 18 mg, about 18 mg to about 20 mg, about 20 mgto about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg,about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mgto about 50 mg.

Idazoxan

Idazoxan has the chemical name2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole. Apharmaceutically acceptable salt of idazoxan (e.g., idazoxanhydrochloride) may be used. Idazoxan may be administered via routesknown in the art, such as by oral administration. The amount of idazoxanor a pharmaceutically acceptable salt thereof administered to thepatient can be in the range of, for example, about 0.1 mg to about 100mg per day. In certain embodiments, idazoxan is administered (e.g.,orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg,about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mgto about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0mg, about 3.0 mg to about 3.5 mg, about 3.5 mg to about 4.0 mg, about4.0 mg to about 4.5 mg, about 4.5 mg to about 5.0 mg, about 5.0 mg toabout 6.0 mg, about 6.0 mg to about 7.0 mg, about 7.0 mg to about 8.0mg, about 8.0 mg to about 9.0 mg, about 9.0 mg to about 10 mg, about 10mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mgto about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg,about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg toabout 80 mg, about 80 mg to about 90 mg, or about 90 mg to about 100 mg.

Prazosin

Prazosin has the chemical name1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine.A pharmaceutically acceptable salt of prazosin may be used. For example,the hydrochloride salt of prazosin is commercially available under thetrademark MINIPRESS® in capsule form. Prazosin may be administered viaroutes known in the art, such as by oral administration. The amount ofprazosin or a pharmaceutically acceptable salt thereof administered tothe patient can be in the range of, for example, about 0.1 mg to about100 mg per day. In certain embodiments, prazosin is administered (e.g.,orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg,about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mgto about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg to about 3.0mg, about 3.0 mg to 4.0 mg, about 4.0 mg to about 5.0 mg, about 5.0 mgto about 7.0 mg, about 7.0 mg to about 9.0 mg, about 9.0 mg to about 15mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mgto about 35 mg, about 35 mg to about 45 mg, about 45 mg to about 60 mg,about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg toabout 90 mg, or about 90 mg to about 100 mg.

Silodosin

Silodosin has the chemical name2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carboxamideand is commercially available under the trademark RAPAFLO® in capsuleform. A pharmaceutically acceptable salt of silodosin (e.g., silodosinhydrochloride) may be used. Silodosin may be administered via routesknown in the art, such as by oral administration. The amount ofsilodosin or a pharmaceutically acceptable salt thereof administered tothe patient can be in the range of, for example, about 0.1 mg to about50 mg per day. In certain embodiments, silodosin is administered (e.g.,orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg,about 0.5 mg to about 1.0 mg, about 1.0 mg to about 2.0 mg, about 2.0 mgto about 3.0 mg, about 3.0 mg to about 4.0 mg, about 4.0 mg to about 5.0mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 7.0 mg, about7.0 mg to about 8.0 mg, about 8.0 mg to 10 mg, about 10 mg to about 15mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mgto about 35 mg, about 35 mg to about 45 mg, or about 45 mg to about 50mg. In certain other embodiments, silodosin is administered (e.g.,orally) at a daily dosage ranging from about 2.0 mg to about 6.0 mg,about 3.0 mg to about 5.0 mg, or about 3.5 mg to about 4.5 mg. In yetcertain other embodiments, silodosin is administered (e.g., orally) at adaily dosage ranging from about 6.0 mg to about 10 mg, about 7.0 mg toabout 9.0 mg, or about 7.5 mg to about 8.5 mg.

Tamsulosin

Tamsulosin has the chemical name5-[(2R)-2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide.A pharmaceutically acceptable salt of tamsulosin may be used. Forexample, the hydrochloride salt of tamsulosin is commercially availableunder the trademark FLOMAX® in capsule form. Tamsulosin may beadministered via routes known in the art, such as by oraladministration. The amount of tamsulosin or a pharmaceuticallyacceptable salt thereof administered to the patient can be in the rangeof, for example, about 0.05 mg to about 10 mg per day. In certainembodiments, tamsulosin is administered (e.g., orally) at a daily dosageranging from about 0.05 mg to about 0.10 mg, about 0.10 mg to about 0.20mg, about 0.20 mg to about 0.30 mg, about 0.30 mg to about 0.40 mg,about 0.40 mg to about 0.50 mg, about 0.50 mg to about 0.60 mg, about0.60 mg to about 0.70 mg, about 0.70 mg to about 0.80 mg, about 0.80 mgto about 0.90 mg, about 0.90 mg to about 1.0 mg, about 1.0 mg to about1.5 mg, about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5 mg,about 2.5 mg to about 3.0 mg, about 3.0 mg to about 4.0 mg, about 4.0 mgto about 5.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 8.0mg, or about 8.0 mg to about 10 mg. In certain other embodiments,tamsulosin is administered (e.g., orally) at a daily dosage ranging fromabout 0.20 mg to about 0.60 mg, about 0.30 mg to about 0.50 mg, or about0.35 mg to about 0.45 mg. In yet certain other embodiments, tamsulosinis administered (e.g., orally) at a daily dosage ranging from about 0.60mg to about 1.0 mg, about 0.70 mg to about 0.90 mg, or about 0.75 mg toabout 0.85 mg.

Terazosin

Terazosin has the chemical name1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl]piperazine.A pharmaceutically acceptable salt of terazosin (e.g., terazosinhydrochloride or terazosin hydrochloride dihydrate) may be used. Forexample, the hydrochloride salt of terazosin is commercially availableunder the trademark HYTRIN® in capsule form. Terazosin may beadministered via routes known in the art, such as by oraladministration. The amount of terazosin or a pharmaceutically acceptablesalt thereof administered to the patient can be in the range of, forexample, about 0.1 mg to about 50 mg per day. In certain embodimentsterazosin is administered (e.g., orally) at a daily dosage ranging fromabout 0.1 mg to about 0.5 mg, about 0.5 mg to about 1.0 mg, about 1.0 mgto about 1.5 mg, about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5mg, about 2.5 mg to about 3.0 mg, about 3.0 mg to about 3.5 mg, about3.5 mg to about 4.0 mg, about 4.0 mg to about 4.5 mg, about 4.5 mg toabout 5.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 7.0mg, about 7.0 mg to about 8.0 mg, about 8.0 mg to about 9.0 mg, about9.0 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, or about40 mg to 50 mg. In certain other embodiments terazosin is administered(e.g., orally) at a daily dosage ranging from about 0.5 mg to about 1.5mg, about 0.8 mg to about 1.2 mg, or about 0.9 mg to about 1.1 mg. Incertain other embodiments, terazosin is administered (e.g., orally) at adaily dosage ranging from about 1.5 mg to about 2.5 mg, about 1.8 mg toabout 2.2 mg, or about 1.9 mg to about 2.1 mg.

Tolazoline

Tolazoline has the chemical name4,5-dihydro-2-(phenylmethyl)-1H-imidazole. A pharmaceutically acceptablesalt of tolazoline (e.g., tolazoline hydrochloride) may be used.Tolazoline may be administered via routes known in the art, such as byintravenous injection. The amount of tolazoline or a pharmaceuticallyacceptable salt thereof administered to the patient can be in the rangeof, for example, about 1 mg/kg body weight to about 100 mg/kg bodyweight per 24 hour period. In certain embodiments, tolazoline isadministered (e.g., intravenously) at a total daily dosage ranging fromabout 1 mg/kg body weight to about 2 mg/kg body weight, about 2 mg/kgbody weight to about 3 mg/kg body weight, about 3 mg/kg body weight toabout 5 mg/kg body weight, about 5 mg/kg body weight to about 7 mg/kgbody weight, about 7 mg/kg body weight to about 9 mg/kg body weight,about 9 mg/kg body weight to about 10 mg/kg body weight, about 10 mg/kgbody weight to about 20 mg/kg body weight, about 20 mg/kg body weight toabout 30 mg/kg body weight, about 30 mg/kg body weight to about 40 mg/kgbody weight, about 40 mg/kg body weight to about 60 mg/kg body weight,about 60 mg/kg body weight to about 80 mg/kg body weight, or about 80mg/kg body weight to about 100 mg/kg body weight.

Yohimbine

Yohimbine has the chemical name(16α,17α)-17-hydroxyyohimban-16-carboxylic acid methyl ester. Apharmaceutically acceptable salt of yohimbine (e.g., yohimbinehydrochloride) may be used. Yohimbine may be administered via routesknown in the art, such as by oral administration. The amount ofyohimbine or a pharmaceutically acceptable salt thereof administered tothe patient can be in the range of, for example, about 1 mg to about 50mg per day. In certain embodiments yohimbine is administered (e.g.,orally) at a daily dosage ranging from about 1.0 mg to about 2.0 mg,about 2.0 mg to about 3.0 mg, about 3.0 mg to about 4.0 mg, about 4.0 mgto about 5.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 7.0mg, about 7.0 mg to about 8.0 mg, about 8.0 mg to about 9.0 mg, about9.0 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45mg, or about 45 mg to about 50 mg.

Additional exemplary alpha-adrenergic receptor antagonists include, forexample, amosulalol, arotinolol, dapiprazole, ergoloid mesylates,fenspiride, indoramin, labetalol, naftopidil, nicergoline,phenoxybenzamine, phentolamine, typical and atypical antipsychotics,atipamezole, and pharmaceutically acceptable salts thereof.

It is appreciated that the alpha-adrenergic receptor antagonist may beadministered by traditional routes of administration known in the art.Certain routes of administration may be preferred for a particulartherapeutic agent, such as where a particular route of administrationreduces first-pass metabolism or has improved bioavailability. Incertain embodiments, the alpha-adrenergic receptor antagonist isadministered orally, transdermally, intradermally, or by transmucosaladministration alone or together in admixture with desmopressin. In yetother embodiments, the alpha-adrenergic receptor antagonist isadministered orally.

The method may also be characterized according to the time periodbetween the start of administration of desmopressin and administrationof the alpha-adrenergic receptor antagonist. In certain embodiments, thefirst administration of desmopressin may coincide with administration ofthe alpha-adrenergic receptor antagonist. Alternatively, the start ofadministration of desmopressin may be before or after the start ofadministration of the alpha-adrenergic receptor antagonist. In certainembodiments, the alpha-adrenergic receptor antagonist is administeredwithin 1 hour of the start of desmopressin administration. In certainembodiments, the alpha-adrenergic receptor antagonist is administeredwithin 0.5 hours, 1 hour, 1.5 hours, or 2 hours of the start ofdesmopressin administration.

5-Alpha Reductase Inhibitors

5-Alpha reductase inhibitors are a class of medicinal agents thatinhibit the activity of 5-alpha reductase. Examplary 5-alpha reductaseinhibitors include, for example, dutasteride, epristeride, finasteride,izonsteride, turosteride, AS-601811, FK143, TF-505, and pharmaceuticallyacceptable salts thereof. A brief description of potentially suitable5-alpha reductase inhibitors is provided below.

Dutasteride

Dutasteride has the chemical name (5α, 17β)-N-{2,5bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide andis commercially available as a soft gelatin capsule under the trade nameAVODART®. A pharmaceutically acceptable salt of dutasteride may be used.Dutasteride may be administered via routes known in the art, such as byoral administration. The amount of dutasteride or pharmaceuticallyacceptable salt thereof administered to the patient can be in the rangeof, for example, about 0.1 mg to about 5 mg per day. In certainembodiments, dutasteride is administered (e.g., orally) at a dailydosage ranging from about 0.1 to about 1 mg, about 1 mg to about 2 mg,about 2 mg to about 3 mg, about 3 mg to about 4 mg, or about 4 mg toabout 5 mg. In certain other embodiments, dutasteride is administered(e.g., orally) at a daily dosage ranging from or about 0.3 mg to about0.7 mg. The currently preferred dose for an adult male is less than therecommended dose for treatment of BPH, namely, less than 0.5 mg/day,e.g., 0.1 to 0.3 or 0.4 mg/day.

Epristeride

Epristeride has the chemical name17β-(N-tert-butylcarboxamido)androsta-3,5-diene-3-carboxylic acid. Apharmaceutically acceptable salt of epristeride may be used. The amountof epristeride or pharmaceutically acceptable salt thereof administeredto the patient can be in the range of, for example, about 1 mg to about500 mg. In certain embodiments, epristeride is administered at a dailydosage ranging from about 0.1 mg to about 1 mg, about 1 mg to about 2mg, about 2 mg to about 5 mg, about 5 mg to about 10 mg, about 1 mg toabout 50 mg, about 50 to about 100 mg, about 100 mg to about 150 mg,about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mgto about 300 mg, about 300 mg to about 350 mg, about 350 mg to about 400mg, about 400 mg to about 450 mg, or about 450 mg to about 500 mg.

Finasteride

Finasteride has the chemical nameN-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamideand is commercially available in tablet form under the trade namePROPECIA®. A pharmaceutically acceptable salt of finasteride may beused. Finasteride may be administered via routes known in the art, suchas by oral administration. The amount of finasteride or pharmaceuticallyacceptable salt thereof administered to the patient can be in the rangeof, for example, from about 0.2 mg to about 20 mg per day. In certainembodiments, finasteride is administered (e.g., orally) at a dailydosage ranging from about 0.2 mg to about 0.5 mg, about 0.5 mg to about1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg toabout 5 mg. In certain other embodiments, finasteride is administered(e.g., orally) at a daily dosage ranging from about 1 mg to about 5 mg.The currently preferred dose of Finasteride for an adult male incombination with desmopressin is less than the recommended Finasteridedose for treatment of BPH, namely, less than 5 mg/day, e.g., about 1 to3 or 4 mg/day. Less than 1.0 mg/day often works well and avoids mostadverse side effects.

AS-601811

AS-601811 has the chemical name4,8-dimethyl-2,3,5,6-tetrahydro-1H-benzo[c]quinolizin-3-one. Apharmaceutically acceptable salt of AS-601811 may be used. The amount ofAS-601811 or pharmaceutically acceptable salt thereof administered tothe patient can be in the range of, for example, about 1 mg to about 500mg. In certain embodiments, AS-601811 is administered at a daily dosageranging from about 1 mg to about 50 mg, about 50 to about 100 mg, about100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg toabout 250 mg, about 250 mg to about 300 mg, about 300 mg to about 350mg, about 350 mg to about 400 mg, about 400 mg to about 450 mg, or about450 mg to about 500 mg.

Izonsteride

Izonsteride has the chemical name(4aR,10bR)-8-((4-ethyl-2-benzothiazolyl)thio)-1,4,4a,5,6,10b-hexahydro-4,10b-dimethylbenzo[f]quinolin-3-(2H)-one.A pharmaceutically acceptable salt of izonsteride may be used. Theamount of izonsteride or pharmaceutically acceptable salt thereofadministered to the patient can be in the range of, for example, about 1mg to about 500 mg. In certain embodiments, izonsteride is administeredat a daily dosage ranging from about 1 to about 50 mg, about 50 to about100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg,about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mgto about 350 mg, about 350 mg to about 400 mg, about 400 mg to about 450mg, or about 450 mg to about 500 mg.

Turosteride

Turosteride has the chemical name1,3-diisopropyl-1-((4-methyl-3-oxo-4-aza-5alpha-androstan-17beta-yl)carbonyl)urea. A pharmaceutically acceptablesalt of turosteride may be used. The amount of turosteride orpharmaceutically acceptable salt thereof administered to the patient canbe in the range of, for example, about 1 mg to about 500 mg. In certainembodiments, turosteride is administered at a daily dosage ranging fromabout 1 mg to about 50 mg, about 50 to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 300 mg to about 350 mg, about350 mg to about 400 mg, about 400 mg to about 450 mg, or about 450 mg toabout 500 mg.

FK143

FK143 has the chemical name4-[3-[3-[bis(4-isobutylphenyl)methyl-amino]benzoyl]-1H-indol-1-yl]butyricacid. A pharmaceutically acceptable salt of FK143 may be used. Theamount of FK143 or pharmaceutically acceptable salt thereof administeredto the patient can be in the range of, for example, about 1 mg to about500 mg. In certain embodiments, FK143 is administered at a daily dosageranging from about 1 mg to about 50 mg, about 50 to about 100 mg, about100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg toabout 250 mg, about 250 mg to about 300 mg, about 300 mg to about 350mg, about 350 mg to about 400 mg, about 400 mg to about 450 mg, or about450 mg to about 500 mg.

TF-505

TF-505 has the chemical name(−)-(S)-4-[1-[4-[1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyricacid. A pharmaceutically acceptable salt of TF-505 may be used. TF-505may be administered via routes known in the art, such as by oraladministration. The amount of TF-505 or pharmaceutically acceptable saltthereof administered to the patient can be in the range of, for example,from about 10 mg to 100 mg per day. In certain embodiments, TF-505 isadministered (e.g., orally) at a daily dosage ranging from about 1 mg toabout 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg,about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg toabout 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg,about 80 mg to about 90 mg, or about 90 mg to about 100 mg. In certainother embodiments, TF-505 is administered (e.g., orally) at a dailydosage ranging from about 25 mg to about 50 mg.

It is appreciated that more than one 5-alpha reductase inhibitor can beadministered to a subject. For example, in certain embodiments,dutasteride and a pharmaceutically acceptable salt of tamsulosin (e.g.,tamsulosin hydrochloride) are administered to the subject. Capsulescontaining dutasteride and tamsulosin hydrochloride are commerciallyavailable under the trademark JALYN®.

Patient Populations

The methods are contemplated to provide a therapeutic benefit to humansubjects, preferably adult males or females, often adults over 50 yearsof age, suffering from disorders associated with or featuringundesirable voiding of a patient's bladder. Exemplary disorders includenocturia, incontinence, enuresis, and diabetes insipidus. In certainembodiments, the human subject suffers from nocturia.

Restoration of Urine Production

The methods can be further characterized according to the time periodrequired in order for the subject to resume normal urine productionafter terminating administration of the desmopressin andalpha-adrenergic receptor antagonist. It is important for the subject toresume normal urine production on a daily basis so that proper fluidbalance is maintained and waste can be excreted through urination.Accordingly, in certain embodiments, the method is further characterizedin that urine production in the human subject is restored within abouttwo hours after administration of desmopressin has been terminated. Incertain other embodiments, the method is further characterized in thaturine production in the human subject is restored within about one hourafter administration of desmopressin has been terminated.

Exemplary Benefits of the Combination Therapy

The methods and compositions are contemplated to provide variousbenefits. One contemplated benefit is improved efficacy in inhibitingthe urge to urinate in a human subject when desmopressin is administeredwith an alpha-adrenergic receptor antagonist compared to the efficacyobserved when desmopressin is administered alone. In certainembodiments, the improvement may be a 5%, 10%, 20%, 30%, 50%, 75%, 100%,or greater improvement in inhibiting the urge to urinate in a humansubject when desmopressin is administered with an alpha-adrenergicreceptor antagonist compared to the efficacy observed when desmopressinis administered alone.

Another contemplated benefit is a reduction in side effects associatedwith administration of desmopressin. This is achieved mostly bypermitting lower doses of desmopressin to be used while still achievingsuccessful reduction in urge to urinate. In certain embodiments, thereduction in side effects is greater in a human subject whendesmopressin is administered with an alpha-adrenergic receptorantagonist compared to the side effects observed when desmopressin isadministered alone at a dosage necessary to achieve a similartherapeutic effect.

The administration of desmopressin and an alpha-adrenergic receptorantagonist may result in a synergistic effect, e.g., a synergisticimprovement in efficacy in inhibiting the urge to urinate in a humansubject. In certain embodiments, the synergistic improvement in efficacyis at least a 5%, 10%, 15%, 20%, 25%, 30%, or greater improvement inefficacy compared to the additive improvement in efficacy associatedwith administration of desmopressin and an alpha-adrenergic receptorantagonist together. Clinical testing of use of the combinations of thetypes disclosed and claimed herein have already demonstrated excellentefficacy and safety, and additional testing is underway.

II. Pharmaceutical Compositions and Dosing Considerations

Another aspect of the invention provides a pharmaceutical compositioncomprising one or more therapeutic agents described herein and apharmaceutically acceptable carrier. The pharmaceutical compositions maybe specially formulated for administration in solid or liquid form,including those adapted for the following: (1) oral administration, forexample, drenches (aqueous or non-aqueous solutions or suspensions),tablets (e.g., those targeted for buccal, sublingual, and/or systemicabsorption), boluses, powders, granules, pastes for application to thetongue; (2) parenteral administration by, for example, subcutaneous,intramuscular, intravenous or epidural injection as, for example, asterile solution or suspension, or sustained-release formulation; (3)topical application, for example, as a cream, ointment, or acontrolled-release patch or spray applied to the skin; (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.Further description of exemplary excipients and formulations designedfor a particular route of administration are described below.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising desmopressin, an alpha-adrenergic receptorantagonist, and a pharmaceutically acceptable carrier. Thealpha-adrenergic receptor antagonist may be, for example, alfuzosin,amosulalol, arotinolol, dapiprazole, doxazosin, ergoloid mesylates,fenspiride, idazoxan, indoramin, labetalol, naftopidil, nicergoline,prazosin, silodosin, tamsulosin, terazosin, tolazoline, yohimbine,phenoxybenzamine, phentolamine, atipamezole, or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the pharmaceuticalcomposition is formulated for nasal administration to a human subject.

The phrase “pharmaceutically-acceptable carrier” means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient. The selected dosagelevel will depend upon a variety of factors including the activity ofthe particular compound of the present invention employed, or the saltthereof, the route of administration, the time of administration, therate of excretion or metabolism of the particular compound beingemployed, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular compound employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

A physician having ordinary skill in the art can readily determine andprescribe the effective amount of the pharmaceutical compositionrequired. For example, the physician could start doses of the compoundsof the invention employed in the pharmaceutical composition at levelslower than that required in order to achieve the desired therapeuticeffect and gradually increase the dosage until the desired effect isachieved.

III. Medical Kits

Another aspect of the invention provides a kit for inhibiting the urgeto urinate in a human subject or inducing an antidiuretic effect in ahuman subject. The kit comprises (i) instructions for use (ii)desmopressin and (iii) an alpha-adrenergic receptor antagonist, presentin mixture or separately, and if separate, administered differently,e.g., orally for the antagonist and transmucosally or by way of a skinpatch for the desmopressin.

The description above describes multiple aspects and embodiments of theinvention, including therapeutic methods, pharmaceutical compositions,and medical kits. The patent application specifically contemplates allcombinations and permutations of the aspects and embodiments.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1

A clinical study was performed to evaluate the impact of administeringdesmopressin in combination with an alpha-adrenergic receptor antagonistalone or together with a 5-alpha reductase inhibitor to reduce theoccurrence of nocturnal voiding by a patient. Experimental proceduresand results are described below. The results show that administration ofdesmopressin in combination with an alpha-adrenergic receptor antagonistalone or together with a 5-alpha reductase inhibitor results in agreater percentage of patients experiencing a reduction in theoccurrence of nocturnal voiding compared to administration ofdesmopressin alone, the alpha-adrenergic receptor antagonist alone, orthe alpha-adrenergic receptor antagonist together with a 5-alphareductase inhibitor.

Part I—Experimental Procedures

Patients in the study met the following criteria: (a) male or femalethat were at least 50 years old and experiencing on average at least twonocturnal voids per night for a duration of at least six months, and (b)do not suffer from any of congestive heart failure, diabetes insipidus,renal insufficiency, hepatic insufficiency, incontinence, illnessrequiring systemic steroids, malignancy within the past 5 years, sleepapnea, nephrotic syndrome, unexplained pelvic mass, urinary bladderneurological dysfunction, have undergone urinary bladder surgery orradiotherapy, or are pregnant or breast feeding.

Patients received as a nasal spray either (i) a 1.5 μg dosage ofdesmopressin or (ii) placebo. The desmopressin nasal spray (or placebo)was administered daily just prior to bedtime for a duration of twelveweeks. In addition, patients previously diagnosed as suffering frombenign prostatic hyperplasia (BPH) and receiving an alpha-adrenergicreceptor antagonist alone or together a 5-alpha reductase inhibitor fortreatment of BPH continued to receive the alpha-adrenergic receptorantagonist alone or together the 5-alpha reductase inhibitor at the samedosage and frequency used prior to enrollment in this study. Allpatients in this study who received an alpha-adrenergic receptorantagonist alone or together a 5-alpha reductase inhibitor for treatmentof their BPH had been receiving the alpha-adrenergic receptor antagonistalone or together the 5-alpha reductase inhibitor for at least 2 monthsbefore enrollment in this study and experienced on average at least twonocturnal voids per night before enrollment in this study. Thedesmopressin nasal spray was prepared by combining aliquots of anEmulsion Stock Solution and a Buffer Solution as described below.

Emulsion Stock Solution:

To produce an emulsion stock solution, the following ingredients inparts by weight are added to a vessel equipped with a stirring bar, andmixed for 15 minutes at 60-65° C.: (i) 180 parts sorbitan monolaurate(Span-20) aqueous solution (12 mg/mL); (ii) 30 parts Polysorbate 20(Tween-20) aqueous solution (2 mg/mL); (iii) 400 parts cottonseed oilaqueous emulsion (26.6 mg/mL); (iv) 600 parts cyclopentadecanolide(CPE-215) aqueous emulsion (40 mg/mL); and (v) water to produce 1,500grams total batch size. After mixing, the preparation is homogenizedusing a high speed mixture at 6500 RPM+ for 20-25 minutes to produce afine emulsion. This solution is autoclaved to assure sterility.

Buffer Solution:

To produce a citric acid buffer stock solution, the followingingredients in parts by weight are added to a vessel equipped with astirring bar, and mixed for 5 minutes at 60-65° C.: (i) 6200 partswater; (ii) 16 parts anhydrous citric acid aqueous solution (1.85mg/mL); (iii) 76 parts sodium citrate, dihydrate aqueous solution (8.9mg/mL); (iv) 104 parts Polysorbate 20 (Tween-20) aqueous solution (12mg/mL); and (v) water to produce 8,500 grams total batch size.

Desmopressin Stock Solution:

To produce a desmopressin stock solution, 0.111 part desmopressinacetate trihydrate is added to sufficient buffer stock solution toproduce 100.0 mL of solution, and stirred until all the desmopressin isdissolved to produce a stock solution having a concentration of 100 μgdesmopressin/mL. From this stock solution a 30 μg/mL solution wasprepared by dilution.

Desmopressin Nasal Spray:

To produce the desmopressin nasal spray, aliquots of the 30 μg/mLsolution were filtered to eliminate any bacterial contamination anddiluted with an equal volume of emulsion stock solution to produceaseptic, preservative free dose forms comprising 15 μg/mL desmopressin,pH 5.5, containing 2% cyclopentadecanolide. These were bottled insterile pump spray bottles fitted with a Pfeiffer APF pump sprayers thatdeliver 100 μL per metered spray (i.e., 1.5 μg desmopressin (i.e., 1500ng desmopressin) per spray). The liquid contains no detectablemicroorganisms.

Patients recorded the occurrence of nocturnal voids during the studyperiod. Patients were designated to be a “Responder” if after receivingtreatment there was a reduction in the average number of nocturnal voidsduring the treatment period. Patients that did not experience areduction in the average number of nocturnal voids during the treatmentperiod were designated to be a “Non-Responder.”

Part II—Results

Results of the clinical study are shown in Tables 1-4 below. Table 1shows results of administering desmopressin or a placebo to BPH patientsreceiving an alpha-adrenergic receptor antagonist alone or together witha 5-alpha reductase inhibitor. The absolute response rate of BPHpatients treated with desmopressin in combination with analpha-adrenergic receptor antagonist alone or together with a 5-alphareductase inhibitor was 57% compared to 26% for that group treated withplacebo (i.e., no desmopressin). This is a difference of 31%.

TABLE 1 BPH PATIENTS RECEIVING DESMOPRESSIN COMBO THERAPY OR ONLY ANALPHA-ADRENERGIC RECEPTOR ANTAGONIST ALONE OR TOGETHER WITH A 5- ALPHAREDUCTASE INHIBITOR Responder Patients Non-Responder Patients Number ofNumber of Number of Number of Patients that Patients Patients thatPatients Second (or Received that Received that Third) Component Desmo-Received Desmo- Received of Combination pressin Placebo pressin PlaceboTherapy (n = 21) (n = 27) (n = 21) (n = 27) alpha-adrenergic 7 6  7** 15receptor antagonist alpha-adrenergic 5 1 2  5 receptor antagonist and5-alpha reductase inhibitor Total Number of 12  7 9 20 Patients PercentTotal 57% 26% 43% 74% (12/21) (7/27) (9/21) (20/27) **One patient wastaking an alpha adrenergic receptor antagonist and an anticholinergicagent.

Table 2 shows results of administering desmopressin or a placebo topatients diagnosed with BPH, but which did not receive analpha-adrenergic receptor antagonist alone or together with a 5-alphareductase inhibitor. The absolute response rate of BPH patientsreceiving desmopressin (i.e., no alpha-adrenergic receptor antagonist or5-alpha reductase inhibitor) was 43% compared to 29% for that group onplacebo (i.e., none of desmopressin, an alpha-adrenergic receptorantagonist, or a 5-alpha reductase inhibitor). This is a difference of14%.

TABLE 2 BPH PATIENTS RECEIVING DESMOPRESSIN OR PLACEBO ResponderPatients Non-Responder Patients Number of Number of Number of Number ofPatients that Patients Patients that Patients Second (or Received thatReceived that Third) Component Desmo- Received Desmo- Received ofCombination pressin Placebo pressin Placebo Therapy (n = 42) (n = 56) (n= 42) (n = 56) none 18 16 24 40 Percent Total 43% 29% 57% 71%

Table 3 shows results of administering desmopressin or a placebo to malepatients that did not have BPH and, therefore, were not receiving analpha-adrenergic receptor antagonist alone or together with a 5-alphareductase inhibitor. The absolute response rate of male patients withoutBPH receiving desmopressin was 53% compared to 35% for that group onplacebo (i.e., no desmopressin). This is a difference of 18%.

TABLE 3 MALE PATIENTS WITHOUT BPH THAT RECEIVED DESMOPRESSIN OR PLACEBOResponder Patients Non-Responder Patients Number of Number of Number ofNumber of Patients that Patients Patients that Patients Second (orReceived that Received that Third) Component Desmo- Received Desmo-Received of Combination pressin Placebo pressin Placebo Therapy (n = 34)(n = 23) (n = 34) (n = 23) none 18 8 16 15 Percent Total 53% 35% 47% 65%

In sum, patients receiving the combination therapy (i.e., desmopressinin combination with an alpha-adrenergic receptor antagonist alone ortogether with a 5-alpha reductase inhibitor) had a higher absoluteresponse rate and a higher relative response rate than patientsreceiving placebo, compared to the response rates observed for (i) BPHpatients receiving only desmopressin, and (ii) male patients without BPHreceiving only desmopressin. This is illustrated in Table 4 below.

TABLE 4 DATA ANALYSIS Difference in Responder Absolute Response ResponseRate Between Rate for Patients Desmopressin-treated Receiving Patients &Those Patient Population Desmopressin Receiving Placebo Responderpatients 57% 31% suffering from BPH and which received alpha- adrenergicreceptor antagonist alone or together with a 5-alpha reductaseinhibitor. Responder patients 43% 14% suffering from BPH that did notreceive an alpha- adrenergic receptor antagonist or 5- alpha reductaseinhibitor. Responder patients 53% 18% that were male and had not beendiagnosed with BPH and were not receiving a 5- alpha reductase inhibitoror an alpha-adrenergic receptor antagonist

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A method of inhibiting the urge to urinate in an adult human subjectover an interval of about two hours to no more than about eight hours,comprising administering to an adult human subject in need thereof aneffective, low dose amount of desmopressin and an alpha-adrenergicreceptor antagonist so that both exert physiological activity during anoverlapping time period.
 2. The method of claim 1, wherein the methodinhibits the urge to urinate in a human subject over an interval ofabout 4 hours to about 7 hours.
 3. The method of claim 1, wherein anantidiuretic effect is achieved over an interval of about two hours tono more than about six hours.
 4. The method of claim 1, wherein anantidiuretic effect is achieved over an interval of about four hours tono more than about seven hours.
 5. The method of claim 1, wherein theadministering achieves in the subject a blood plasma concentration ofdesmopressin that does not exceed 10 or 15 pg/mL.
 6. The method of claim1, wherein the administering achieves in the subject a blood plasmaconcentration of desmopressin in the range of about 0.5 pg/mL to about 5pg/mL.
 7. The method of claim 1, wherein the administering achieves inthe human subject a blood plasma concentration of desmopressin in therange of about 0.5 pg/mL to about 2.5 pg/mL.
 8. The method of claim 1,wherein desmopressin is administered transdermally, intradermally, ortransmucosally across the oral or nasal mucosa.
 9. The method of claim1, wherein desmopressin is administered transdermally or intradermally.10. The method of claim 1, wherein desmopressin is administeredintranasally.
 11. The method of claim 1, wherein desmopressin isadministered sublingually across the oral mucosa.
 12. The method ofclaim 9, wherein desmopressin is administered at a flux rate rangingfrom about 5 ng/hour to about 35 ng/hour.
 13. The method of claim 9,wherein desmopressin is administered at a flux rate ranging from about 5ng/hour to about 15 ng/hour.
 14. The method of claim 1, wherein thealpha-adrenergic receptor antagonist is alfuzosin, amosulalol,arotinolol, dapiprazole, doxazosin, ergoloid mesylates, fenspiride,idazoxan, indoramin, labetalol, naftopidil, nicergoline, prazosin,silodosin, tamsulosin, terazosin, tolazoline, yohimbine,phenoxybenzamine, phentolamine, atipamezole, or a pharmaceuticallyacceptable salt thereof.
 15. The method of claim 1, wherein thealpha-adrenergic receptor antagonist is alfuzosin, doxazosin, idazoxan,prazosin, silodosin, tamsulosin, terazosin, tolazoline, yohimbine, or apharmaceutically acceptable salt thereof.
 16. The method of claim 1,wherein the alpha-adrenergic receptor antagonist is alfuzosin,doxazosin, prazosin, silodosin, tamsulosin, terazosin, tolazoline,yohimbine, or a pharmaceutically acceptable salt thereof.
 17. The methodof claim 1, wherein the alpha-adrenergic receptor antagonist isadministered orally, transdermally, intradermally, or across the nasalor oral mucosa.
 18. The method of claim 1, wherein the alpha-adrenergicreceptor antagonist is administered orally.
 19. The method of claim 1,wherein the alpha-adrenergic receptor antagonist is administered within1 hour before or after the start of desmopressin administration.
 20. Themethod of claim 1, wherein the subject suffers from nocturia,incontinence, enuresis, or diabetes insipidus.
 21. The method of claim1, wherein the subject suffers from nocturia.
 22. The method of claim 1,wherein urine production in the human subject is restored within abouttwo hours after administration of desmopressin has been terminated. 23.The method of claim 1, wherein the method comprises administering to theadult human subject an alpha-adrenergic receptor antagonist on a dailybasis for a period of at least a month and administering desmopressinbefore the subject retires to sleep.
 24. The method of claim 1, whereinthe method comprises administering to the adult human subject analpha-adrenergic receptor antagonist at a dose level lower than itssmallest drug label recommended dose for treatment of BPH andadministering desmopressin before the subject retires to sleep.
 25. Themethod of claim 1, wherein the method comprises administering to theadult human subject as a mixture before the subject retires to sleepdesmopressin and an alpha-adrenergic receptor antagonist at a dose levellower than the smallest drug label recommended dose of said antagonistfor treatment of BPH.
 26. The method of claim 1, further comprisingadministering a 5-alpha reductase inhibitor.
 27. The method of claim 26,wherein the 5-alpha reductase inhibitor is dutasteride, epristeride,finasteride, izonsteride, turosteride, AS-601811, FK143, TF-505, or apharmaceutically acceptable salt thereof.
 28. The method of claim 1,wherein the adult human subject is an adult male human.
 29. Apharmaceutical composition comprising desmopressin, an alpha-adrenergicreceptor antagonist, and a pharmaceutically acceptable carrier.
 30. Thepharmaceutical composition of claim 29, wherein the pharmaceuticalcomposition is formulated for intranasal or sublingual administration toa human subject.
 31. The pharmaceutical composition of claim 29, whereinthe alpha-adrenergic receptor antagonist is alfuzosin, amosulalol,arotinolol, dapiprazole, doxazosin, ergoloid mesylates, fenspiride,idazoxan, indoramin, labetalol, naftopidil, nicergoline, prazosin,silodosin, tamsulosin, terazosin, tolazoline, yohimbine,phenoxybenzamine, phentolamine, atipamezole, or a pharmaceuticallyacceptable salt thereof.